Process for producing a stable low concentration, injectable solution of noradrenaline

ABSTRACT

In a first aspect, the present invention relates to a process for producing a stable, injectable solution with low content of noradrenaline, which includes dissolving noradrenaline and optionally an excipient in deoxygenated or degassed water, filtrating the resulting noradrenaline solution in a nitrogen current, distributing the solution in a nitrogen current, and sterilization, preferably hot. The invention further provides a stable, injectable solution with low content of noradrenaline, substantially free of anti-oxidizing and preservative agents, as well as uses thereof in the medical and pharmaceutical fields.

This application is a U.S. national stage of PCT/EP2015/054021 filed on26 Feb. 2015, which claims priority to and the benefit of ItalianApplication No. MI2014A000306 filed on 27 Feb. 2014, the contents ofwhich are incorporated herein by reference in their entireties.Thisapplication is an application for reissue of U.S. application Ser. No.15/118,164, filed Feb. 26, 2015, entitled “Process for producing astable low concentration, injectable solution of noradrenaline,” grantedas U.S. Pat. No. 10,251,848 on Apr. 9, 2019, which is a national stageentry of PCT/EP2015/054021, filed Feb. 26, 2015, which claims priorityto MI2014A0306, filed Feb. 27, 2014. This application is co-pending withU.S. application Ser. Nos. 17/006,838 and 17/006,841, filed Aug. 30,2020, both of which are also applications for reissue of U.S.application Ser. No. 15/118,164, filed Feb. 26, 2015, entitled “Processfor producing a stable low concentration, injectable solution ofnoradrenaline,” granted as U.S. Pat. No. 10,251,848 on Apr. 9, 2019.

FIELD OF THE INVENTION

The present invention relates to a process for producing a stable lowconcentration, injectable solution of noradrenaline.

The present invention originates in the field of pharmaceuticaltechnology and industrial processes for the production of activeingredients.

Specifically, the present invention relates to a process for producingan injectable solution containing noradrenaline at low concentration asactive ingredient, and highly stable, injectable solutions ofnoradrenaline at low concentration, typically obtained with thisprocess.

STATE OF THE ART

Noradrenaline or norepinephrine is a catecholamine or an amine compoundwith the structure similar to that of catechol and having the chemicalformula C₈H₁₁NO₃. From a physiological standpoint, noradrenaline is achemical mediator with sympathomimetic action on the transmission ofnervous impulses at neuroeffector junctions of the sympathetic nervoussystem. Noradrenaline is released at the postganglionicortho-sympathetic (or sympathetic) nerve endings and at adrenal medulla,and acts on both types of adrenergic receptors responsible for theaction of sympathomimetics at the level of various effector organs, butwith prevalence of alpha type actions.

From a pharmacological standpoint, noradrenaline performs manyactivities, mainly confined to the level of the circulatory apparatus.It causes arteriolar vasoconstriction with increased peripheralresistance and blood pressure. Noradrenaline has no particularly evidenteffects on the heart, but can cause, by reflex paths, a decrease of theheart rate through a vagal reflex. Noradrenaline also produces amoderate relaxation of bronchial smooth muscle and gastrointestinalmuscle and modest action at the level of the central nervous system andthe cerebral circle.

From a therapeutic point of view, it is used for its pressor effects inconditions of acute hypotension, particularly if accompanied by loss ofperipheral vascular tone. Typically, the action of noradrenaline isshort-lived, because this molecule is rapidly inactivated in the bodythrough two metabolic pathways: oxidative deamination, operated by theoxidase, and methylation, operated by the methyltransferase.

Noradrenaline is commonly administered in the form of solution, byintravenous slow infusion, and finds application in the case ofcardiovascular collapse, in states of shock associated with lowperipheral resistance, the so-called septic shock, and to restore andmaintain physiological blood pressure levels.

Noradrenaline solutions for injection, at a concentration of 1 mg/ml,are available on the market.

Noradrenaline, such as the catecholamines in general, has the drawbackof being easily decomposable substances, when exposed to oxygen of theair. On contact with oxygen, noradrenaline decomposes giving quinoneby-products, i.e. compounds which impart a strong coloration to thepharmaceutical solution, thus highlighting the denaturation of theactive principle.

In the practice of pharmaceutical technology, this problem is at leastpartially obviated by adding anti-oxidizing agents and/or preservativesto the injectable noradrenaline solutions.

Sulfites are anti-oxidizing agents commonly used to stabilize injectablenoradrenaline solutions. However, the use of sulfites is not withoutdisadvantages, since their presence within the pharmaceuticalformulations is associated with an increased risk of developing allergicor sensitization reactions.

Furthermore, sulfites in an aqueous solution tend to interact withadrenaline through addition reactions. These reactions are acceleratedbecause of the exposure of the solution to heat, such as occurs in thetreatment of high temperature sterilization of injectable solutions.

To overcome these problems, processes were adopted for the production ofnoradrenaline injectable solutions, which took advantage of high vacuumpackaging technologies.

However, available technologies have not proven adequate, in particularwhen applied to processes in which the solution final sterilization stepis performed at high temperature. In fact, these conditions increase therisks of deterioration of the active principle. Presence of oxygen oreven of trace metals in the injectable solution is sufficient todenaturate noradrenaline contained in the aqueous solution.

Currently, there is a need for technologies for the production ofinjectable solutions of noradrenaline at low concentration for medicaluse, which are stable and simple to manufacture.

One of the objects of the present invention is to provide a process forproducing an injectable solution of noradrenaline with low concentrationof active ingredient, that is stable and provided with an improvedcompliance and safety profile for the patient.

A further object is to provide an injectable solution at lowconcentration of noradrenaline, that is highly stable and free ofpreserving agents or anti-oxidizing allergenic agents such as sulphites.

SUMMARY OF THE INVENTION

The Applicant has found that a noradrenaline solution for injection,particularly stable even in the absence of preservatives andanti-oxidizing, is obtained by adopting a combination of specificconditions in the field of pharmaceutical production technology.

According to a general aspect the invention relates to a process forproducing a low concentration injectable noradrenaline solution which ishighly stable in the absence of anti-oxidizing or preservative agents,as defined in any one of claims 1-8.

According to this first aspect there is provided a process for producinga low concentration injectable noradrenaline solution comprising thefollowing steps:

-   -   a. dissolving noradrenaline and optionally an excipient in        deoxygenated or degassed water,    -   b. adjusting the pH of the resulting solution by adding        hydrochloric acid until a value in the range from 3.2-3.6 is        achieved,    -   c. filtrating the resulting noradrenaline solution in an inert        gas current,    -   d. distribution of the solution in a current of an inert gas,    -   e. sterilization of the solution.

In the process of the invention, the oxidation of noradrenaline issubstantially prevented using degassed or deoxygenated water, typicallyby bubbling or blowing a stream of inert gas and performing thesubsequent steps in substantial absence of air or oxygen, through theuse of an inert gas.

The conditions previously reported, combined with acid values of pH ofthe noradrenaline solution, selected in the range from 3.2 to 3.6, inparticular from 3.3 to 3.6, prevent or substantially reduce theoccurrence of oxidation and/or racemization of noradrenaline, thuspreventing its denaturation and the formation of dextrorotatory isomer,which has a reduced therapeutic activity.

The inventors found that, in the specific process conditions accordingto the invention, the noradrenaline solution obtained has a stability atleast equal to that of an injectable solution of equal noradrenalineconcentration added with sulphites, according to the prior art, whileavoiding the risks associated with the use of preservatives.

Furthermore, Applicant found that racemization occurs at pH values lowerthan 3, while it is almost absent at the values selected according tothe invention. Conversely, Applicant found that the incidence ofoxidative phenomena that lead to the formation of the main degradationproduct, i.e. arterenone, increases at pH values higher than 4.

According to another aspect, the present invention provides anoradrenaline injectable solution that is stable, substantially free ofpreservatives, complexing agent and/or anti-oxidizing agent, as definedin any one of claims 9-16.

In certain embodiments of the invention noradrenaline is noradrenalinebase or a pharmaceutically acceptable noradrenaline salt such asnoradrenaline tartrate or bitartrate or bitartrate monohydrate.

According to some embodiments, the stable noradrenaline solution isobtained by the process described above.

According to some preferred embodiments, the injectable solution has alow concentration of noradrenaline, in the range of 0.04 mg/ml to 0.20mg/ml.

According to a further aspect, a stable, injectable solution with acontent of noradrenaline in the range of 0.04 mg/ml to 0.20 mg/ml isprovided, for use in medicine, in particular for the treatment ofcardiac circulatory collapse, in states of shock associated with lowperipheral resistances or to restore and/or keep physiological pressurelevels.

According to a further aspect a method for the treatment of cardiaccirculatory collapse, especially in states of shock associated with lowperipheral resistances or to restore and/or keep physiological pressurelevels is provided said method comprising the administration of aneffective amount of a noradrenaline injectable solution that is stable,substantially free of preservatives and/or anti-oxidizing agents, asdefined in any one of appended claims 9-16.

Typically, the stable noradrenaline solution of the invention isadministered by intravenous or intra-arterial injection. In certainembodiments, there is provided an infusion of a therapeutically activeamount of the above stable noradrenaline solution according to theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The Applicant has identified a process for producing noradrenalineinjectable solutions, in particular at low concentrations, which areparticularly stable in the absence of anti-oxidizing, preservativeand/or complexing agents.

According to certain aspects the invention thus relates to a process forthe production of a noradrenaline injectable solution, in particularwith a content of noradrenaline of 0.04 to 0.20 mg/ml comprising thefollowing steps:

-   -   a. dissolving noradrenaline and optionally an excipient in        deoxygenated or degassed water to give a noradrenaline solution,    -   b. adjusting the pH of the noradrenaline solution by adding an        aqueous solution of hydrochloric acid to reach a pH from 3.2 to        3.6,    -   c. filtrating the noradrenaline solution resulting from step b.        in a current of inert gas, typically nitrogen,    -   d. distributing the noradrenaline solution of step c. in a        current of inert gas, typically nitrogen,    -   e. sterilizing the noradrenaline solution obtained by step d.

According to some embodiments of the invention, the dissolving stepincludes dissolving 0.04 to 0.20 mg of noradrenaline per ml of infusionwater.

Typically, the water used to prepare the solution is degassed ordeaerated, distilled, sterile, pyrogen-free water for pharmaceuticaluse.

According to some embodiments, the deoxygenated or degassed water isobtained by blowing or bubbling an inert gas current, typically based onnitrogen or a noble gas such as argon.

In the process of the invention, any inert gas can be used, such asnitrogen, argon and mixtures thereof, to remove oxygen or air in one ormore of the steps and to limit risks of oxidation of the noradrenalinecontained in the injectable aqueous solution.

Typically, in step a) noradrenaline and any optional excipients isdissolved in water for pharmaceutical sterile preparations, for exampledeaerated or degassed by bubbling or blowing an inert gas. Dissolutioncan be carried out within a suitable inert container, in which air oroxygen have been removed by passage of inert gas. During dissolution ofthe noradrenaline an inert gas can be blown into the container or tankof the solution, to remove any residual oxygen.

According to some embodiments, upon completion of process step a) thenoradrenaline injectable solution obtained has a residual oxygen contentequal to or lower than 100 ppb.

In process step b), the pH of the noradrenaline aqueous solution isfinely adjusted within the selected range of 3.2 to 3.6, preferablywithin a pH range of 3.3 to 3.6, in particular until a value close to3.4 is reached, for example, typically by adding 1N HCl, in order tofurther stabilize the solution, reducing noradrenaline degradation.

The Applicant has indeed verified that pH values of the solution higherthan 3.6 cause an increase of the formation of arterenone, while pHvalues lower than 3.2 have greater incidence in the appearance ofd-noradrenaline.

It was unexpectedly observed that, even a small variation or adjustmentof the pH value of the noradrenaline injectable solution from 3.1 to3.2, even more and especially from 3.1 to 3.3, causes a significantreduction or absence in the racemization of noradrenaline tod-noradrenaline and an increase to the therapeutic activity as well asstability of the injectable solution.

Therefore, the specific conditions of the process of the inventionminimize the formation of arterenone, the main degradation product ofnoradrenaline and enantiomer of d-noradrenaline, which features lowertherapeutic activity.

Step c) of filtration of the process is performed by passing thesolution containing noradrenaline through a filter of the type forsterilization. Passage of the noradrenaline solution through the filtercan be speeded up by blowing a current of inert gas which acts as acarrier.

Suitable filters are those used in the pharmaceutical technology forpreparation of sterile injectable solutions.

In step d), the noradrenaline solution is distributed in suitablecontainers such vials or ampoules depyrogenated preferably in thepresence of inert gas, typically nitrogen, in order to minimize thevolume of residual oxygen in the head of the sealed bottle and toprevent oxidative effects that may affect the stability of the solutionitself.

Carrying out both steps c) and d), respectively for filtration andfilling in nitrogen current, fulfils the main purpose of keeping thevalues of residual oxygen in the noradrenaline injectable solution tovery low levels or oxygen free.

In some embodiments, at the end of step d), the noradrenaline injectablesolution obtained has a residual oxygen content equal to or lower than100 ppb.

The diluted noradrenaline solution sterilization step may beaccomplished by heating, typically at temperatures above 100° C., for atime suitable for sterilization, for example equal to or greater than 15minutes.

Surprisingly, the noradrenaline injectable solution at low concentrationwas stable after sterilization for 15 minutes at 121° C.

The inventors have found that the substantial absence of air or oxygenand the correction of the pH of the solution to a value in the range of3.2 to 3.6, in particular close to 3.4 units, increases the stability ofthe noradrenaline solution, allowing storage at room temperature forlong periods of time, up to 6 months.

According to some aspects of the invention, the steps of the process ofmanufacture are carried out in sterile environments in order to avoidbacterial contamination of the noradrenaline solution.

According to a further aspect the present invention provides anoradrenaline injectable solution stable and substantially free ofpreservatives and/or anti-oxidizing agents, optionally containing anexcipient, in which the concentration of noradrenaline is in the rangeof 0.04 to 0.2 mg/ml and pH is 3.2 to 3.6.

In some embodiments the noradrenaline stable injectable solution issubstantially free of preservatives and/or anti-oxidizing agents and thenoradrenaline concentration is between 0.04 and 0.2 mg/ml, and pH isbetween 3.2 and 3.6, preferably between 3.3 and 3.6.

Within the scope of the invention, by the term “substantially free ofpreservatives and/or anti-oxidizing agents” is meant that preservativesand/or antioxidant agents, if present, are present as impurities,typically in an amount less than 0.005% by weight, as determined byHPLC-MS.

In some embodiments the noradrenaline injectable solution is free ofanti-oxidizing and/or preservative agents.

Typically, the stable, injectable solution is a water-based solution andmay be obtained by a process according to any one of the embodimentspreviously described.

According to some embodiments, the injectable solution of the inventioncontains an excipient, typically NaCl, in particular at a concentrationin the range of 8.2 to 8.6 mg/ml, for example equal to 8.4 mg/ml.

The injectable solution of the invention has a particularly low contentof oxygen dissolved in the solvent water, typically less than 100 ppb.

According to some embodiments, the stable noradrenaline injectablesolution of the invention contains less than 0.05% by weight ofarterenone. According to these and other embodiments of the invention,the stable noradrenaline injectable solution of the invention has anacidic pH selected in the range of 3.2 to 3.6, preferably of 3.3 to 3.6,and may have a content of enantiomer d-noradrenaline equal to or lessthan 5% by weight, with respect to the total weight of active principle(noradrenaline in one of its active forms) present in the solution.

In some embodiments, the injectable solution of the invention has a pHvalue from 3.3 to 3.6 and a content of enantiomer d-noradrenaline equalto or less than 2% by weight or 1% by weight with respect to the totalweight of noradrenaline present in the solution.

According to some embodiments, the noradrenaline contained in theinjectable solution is in the form of a pharmaceutically acceptablesalt, for example, bitartrate.

The noradrenaline injectable solution has a surprising stability, evenat high temperatures. The inventors have conducted studies on thestability at 40° C. with the noradrenaline injectable solutions, andhave found that, in these conditions of temperature, stability lasts atleast 3 months.

With the present invention the inventors have achieved some significantadvantages including a surprising increase of stability in injectablesolutions with a concentration of 0.04 to 0.2 mg/ml and surprisingly lowlevels of impurities with a pH of 3.2-3.6, in particular of 3.3 to 3.6,which determine a significant increase in the product safety profile.

In addition, the low concentration noradrenaline solution issurprisingly stable at room temperature for at least 6 months.

Typically, the low concentration noradrenaline injectable solutions ofthe invention are filled into sterile containers such as vials orampoules in a modified atmosphere, for example in the presence of aninert gas containing basically nitrogen and/or argon.

According to a further aspect, the present invention relates to apharmaceutical composition comprising noradrenaline in a quantity of0.04 to 0.2 mg/ml obtained by a process according to any one of theembodiments previously described, and a pharmaceutically acceptablecarrier and/or excipient.

Pharmaceutically acceptable carriers and excipients include substancescommonly used in the production techniques of pharmaceutical and medicaldevices.

The present invention claims the priority of the Italian patentapplication MI2014A000306 of 27 Feb. 2014, the content of which isentirely incorporated herein by reference.

The present invention is described below, with reference to thefollowing examples, which are provided for illustrative purposes onlyand should not be understood as limiting the present invention.

Example 1

4 diluted solutions of noradrenaline at different concentration werestudied:

-   diluted solution containing 0.04 mg/ml (2 mg/50 ml) of    noradrenaline,-   diluted solution containing 0.06 mg/ml (3 mg/50 ml) of    noradrenaline,-   diluted solution containing 0.12 mg/ml (6 mg/50 ml) of    noradrenaline,-   diluted solution containing 0.20 mg/ml (10 mg/50 ml) of    noradrenaline,

The noradrenaline solutions were prepared using water deoxygenated bynitrification (residual oxygen <100 ppb).

The noradrenaline solutions were obtained with a process which involvedthe following schematic steps:

-   a) dissolving the active principle and the excipients in water    deoxygenated by degassing in a nitrogen current-   b) filtrating the solution in a nitrogen current-   c) distribution of the solution in a nitrogen current,-   d) sterilizing the vials at 121° C. for 15 minutes.

After loading the blender, the water for injections was degassed byboiling and then cooled to 25° C. Sodium chloride and noradrenalinebitartrate were added in this order. The solution was kept understirring, maintaining a constant blowing of nitrogen, for 10 minutes.

-   After 10 minutes, the pH value of the solution was measured and    corrected with 1N hydrochloric acid, until it reached the value of    3.4 units, in any case within the range of 3.2-3.6.

2 mg/50 ml 3 mg/50 ml 6 mg/50 ml 10 mg/50 ml pH 3.4 3.5 3.4 3.5

The solution was filtered under nitrogen pressure in a nitrogen currentand distributed in clear glass 50 ml bottles. The bottles were thensubjected to terminal sterilization in autoclave under overkillconditions (121° C. for 15 minutes).

Tests carried out on the vials after sterilization gave the followingresults:

2 mg/50 ml 3 mg/50 ml 6 mg/50 ml 10 mg/50 ml Color and In In In Intransparency conformity conformity conformity conformity pH of the 3.43.5 3.4 3.5 solution Titer of 99.3% 99.2%  98.8%  98.7% Noradrenaline(HPLC) Titer of Not detected Not detected Not detected <0.05% Arterenone(HPLC) Titer of Not detected Not detected <0.05% <0.05% impurities(HPLC)

Example 2

Stability of Diluted Noradrenaline Solutions

Stability: 4 batches with concentration of noradrenaline respectively of0.04 mg/ml, 0.06 mg/ml, 0.12 mg/ml, 0.20 mg/ml were placed at 25° C. and40° C.

After 6 months at 25° C. and 3 months at 40° C., the solutions wereunchanged from a physico-chemical point of view.

The titer of noradrenaline remains above 90%. Arterenone impurity wasalways below 0.2% and the total of other impurities was less than 0.5%.The enantiomer concentration remains always lower than 10%.

Example 3

Low Concentration Noradrenaline Injectable Solutions

Noradrenaline 0.04 mg/ml Pro 1 ml Pro 50 ml Noradrenaline Bitartrate0.08* mg 4.00* mg Sodium Chloride 8.4 mg 420.0 mg Hydrochloric acid q.s.ad q.s. ad pH 3.3-3.6 pH 3.3-3.6 Water for injections ad 1 ml ad 50 ml*Corresponding respectively to 0.04 mg and 2.00 mg of noradrenaline base

Example 4

Low Concentration Noradrenaline Injectable Solutions

Noradrenaline 0.06 mg/ml Pro 1 ml Pro 50 ml Noradrenaline Bitartrate0.12* mg 6.00* mg Sodium Chloride 8.4 mg 420.0 mg Hydrochloric acid q.s.ad q.s. ad pH 3.2-3.6 pH 3.2-3.6 Water for injections ad 1 ml ad 50 ml*Corresponding respectively to 0.06 mg and 3.00 mg of noradrenaline base

Example 5

Low Concentration Noradrenaline Injectable Solutions

Noradrenaline 0.12 mg/ml Pro 1 ml Pro 50 ml Noradrenaline Bitartrate0.24* mg 12.00* mg Sodium Chloride 8.4 mg 420.0 mg Hydrochloric acidq.s. ad q.s. ad pH 3.2-3.6 pH 3.2-3.6 Water for injections ad 1 ml ad 50ml *Corresponding respectively to 0.12 mg and 6.00 mg of noradrenalinebase

Example 6

Low Concentration Noradrenaline Injectable Solutions

Noradrenaline 0.2 mg/ml Pro 1 ml Pro 50 ml Noradrenaline Bitartrate0.40* mg 20.0* mg Sodium Chloride 8.4 mg 420.0 Hydrochloric acid q.s. adq.s. ad pH 3.3-3.6 pH 3.3-3.6 Water for injections ad 1 ml ad 50 ml*Corresponding respectively to 0.20 mg and 10.0 mg of noradrenaline base

The invention claimed is:
 1. A stable injectable noradrenaline solutioncomprising noradrenaline, a solvent, an excipient, and hydrochloricacid, wherein the amount of noradrenaline is from 0.04 to 0.2 mg/ml, thesolvent is degassed or deaerated water, the excipient is NaCl, and thepH of the solution is in the range of from 3.3 to 3.6, and wherein thesolution is free of preservatives and anti-oxidizing agents.
 2. Thestable injectable noradrenaline solution according to claim 1, obtainedby a process comprising: a. dissolving noradrenaline and the excipientin deoxygenated or degassed water, to obtain a concentration ofnoradrenaline from 0.04 to 0.20 mg/ml, b. adjusting the pH of theresulting solution by adding hydrochloric acid until a value in therange from 3.3 to 3.6 is achieved, c. filtrating the resultingnoradrenaline solution in an inert gas current, d. distributing thenoradrenaline solution in an inert gas current, e. sterilizing thenoradrenaline solution.
 3. The stable injectable noradrenaline solutionaccording to claim 1, oxygen content is equal to or lower than 100 ppb.4. A stable injectable noradrenaline solution comprising noradrenalineor a pharmaceutically acceptable salt thereof, a solvent, an excipient,and hydrochloric acid, wherein the concentration of noradrenaline orpharmaceutically acceptable salt thereof based on the weight ofnoradrenaline base is less than or equal to 0.2 mg/ml, the solventconsists of degassed or deaerated water, the excipient is NaCl, and thepH of the solution is in the range of from 3.3 to 3.6, and wherein thesolution is free of preservatives and anti-oxidizing agents andcomplexing agents.
 5. The stable injectable noradrenaline solutionaccording to claim 4, in one or more sealed containers, obtained by aprocess comprising: a) dissolving noradrenaline or pharmaceuticallyacceptable salt thereof and the excipient in deoxygenated or degassedwater, to obtain a concentration of noradrenaline or pharmaceuticallyacceptable salt thereof based on the weight of the noradrenaline base ofless than or equal to 0.2 mg/ml, b) adjusting the pH of the resultingsolution by adding hydrochloric acid until a value in the range of from3.3 to 3.6 is achieved, c) filtrating the resulting noradrenalinesolution in an inert gas current, d) distributing the noradrenalinesolution in an inert gas current into said one or more containers, ande) sterilizing the noradrenaline solution, wherein said sterilizingcomprises filtrating, optionally during step (c), or heat sterilizing.6. The stable injectable noradrenaline solution according to claim 4,wherein the solvent has an oxygen content equal to or lower than 100ppb.
 7. The solution of claim 4, wherein, after six months storage at25° C., the solution comprises: a) <0.2% arterenone; b) <0.5% impuritiesother than arterenone; and c) <10% d-noradrenaline; based on the weightof the noradrenaline base.
 8. The solution of claim 5 wherein saidsterilizing comprises filtrating during step (c).
 9. The solution ofclaim 5, wherein the solvent has an oxygen content equal to or lowerthan 100 ppb.
 10. The solution of claim 5, wherein, after six monthsstorage at 25° C., the solution comprises: a) <0.2% arterenone; b) <0.5%impurities other than arterenone; and c) <10% d-noradrenaline; based onthe weight of the noradrenaline base.
 11. The solution of claim 6,wherein, after six months storage at 25° C., the solution comprises: a)<0.2% arterenone; b) <0.5% impurities other than arterenone; and c) <10%d-noradrenaline; based on the weight of the noradrenaline base.
 12. Astable injectable noradrenaline solution comprising noradrenaline or apharmaceutically acceptable salt thereof, a solvent, an excipient, andhydrochloric acid, wherein the concentration of noradrenaline bitartratebased on the weight of noradrenaline base is less than or equal to 0.2mg/ml, the solvent consists of degassed or deaerated water, theexcipient is NaCl, the pH of the solution is in the range of from 3.3 to3.6, and the solution is free of preservatives and anti-oxidizingagents.
 13. The stable injectable noradrenaline solution according toclaim 12, in one or more sealed containers, obtained by a processcomprising: a) dissolving noradrenaline bitartrate and the excipient indeoxygenated or degassed water, to obtain a solution having aconcentration of noradrenaline bitartrate based on the weight of thenoradrenaline base of less than or equal to 0.2 mg/ml, b) adjusting thepH of the solution by adding hydrochloric acid until a value in therange of from 3.3 to 3.6 is achieved, c) filtrating the solution in aninert gas current, d) distributing the solution in an inert gas currentinto said one or more containers, and e) sterilizing the solution,wherein said sterilizing comprises filtrating, optionally during step(c), or heat sterilizing.
 14. The stable injectable noradrenalinesolution according to claim 12, wherein the solvent has an oxygencontent equal to or lower than 100 ppb.
 15. The solution of claim 12,wherein, after six months storage at 25° C., the solution comprises: a)<0.2% arterenone; b) <0.5% impurities other than arterenone; and c) <10%d-noradrenaline; based on the weight of the noradrenaline base.
 16. Thesolution of claim 13 wherein said sterilizing comprises filtratingduring step (c).
 17. The solution of claim 13, wherein the solvent hasan oxygen content equal to or lower than 100 ppb.
 18. The solution ofclaim 13, wherein, after six months storage at 25° C., the solutioncomprises: a) <0.2% arterenone; b) <0.5% impurities other thanarterenone; and c) <10% d-noradrenaline; based on the weight of thenoradrenaline base.
 19. The solution of claim 14, wherein, after sixmonths storage at 25° C., the solution comprises: a) <0.2% arterenone;b) <0.5% impurities other than arterenone; and c) <10% d-noradrenaline;based on the weight of the noradrenaline base.
 20. A container of a lowconcentration injectable noradrenaline bitartrate solution, having anoradrenaline bitartrate concentration less than 1 mg/ml based on theweight of noradrenaline base, produced by a method comprising thefollowing steps in the substantial absence of air or oxygen: a)dissolving noradrenaline bitartrate in deoxygenated or degassed water tomake a solution comprising less than 1 mg/ml noradrenaline bitartratebased on the weight of the noradrenaline base; b) adjusting the pH ofthe solution by adding hydrochloric acid until a value of from 3.3 to3.6 is achieved; c) filtrating the solution in an inert gas current d)distributing the solution into said one or more containers in a currentof an inert gas; and e) sterilizing the solution; wherein: i) saidsterilizing comprises filtrating, optionally during step (c), or heatsterilizing; ii) after six months storage at 25° C., the solutioncomprises: <0.2% arterenone, <0.5% impurities other than arterenone; and<10% d-noradrenaline, based on the weight of the noradrenaline base; andiii) the solution is free of preservatives and anti-oxidizing agents.21. The container of claim 20, wherein said sterilizing comprisesfiltrating during step (c).
 22. The container of claim 20, wherein thesolution is preservative-free, antioxidant-free, and free of complexingagents.
 23. The container of claim 20, wherein the solution comprisesless than or equal to 0.2 mg/ml noradrenaline bitartrate based on theweight of the noradrenaline base.